Cigarette smoking is the leading cause of lung cancer. However, only a small portion of the patients who are smokers ever develop lung cancer. Furthermore, more and more patients who have never smoked also develop lung cancer. The cause of lung cancer for those who have never smoked is unknown. To address this question, we collaborated with Dr. Neil Caporaso and his colleagues at DCEG to examine gene expression profiles using paired lung cancer and normal samples from patients who are current, past, and never smokers. A total of 30 patients with 10 cases from each smoking status group were used and the samples were processed for analysis by the Affymetrix U133 GeneChips. A total 52 samples were analyzable after preprocessing which included 7 tumor and 7 normal lung tissues from never smokers among others. Non-supervised clustering analysis of all samples revealed that 5 of 7 tumors from never-smoking patients grouped together while tumors from current and past smokers were essentially indistinguishable. Our result to date provided strong evidence for two important insights: 1) although clinically distinguishable, a majority of lung cancers from non-smoking patients most likely developed via a different molecular mechanism from those that developed from patients who had smoked. 2) Lung tumors from past smokers are molecularly similar to those of the current smokers and most likely have occurred as a result of the damages caused by smoking.